Paclitaxel and docetaxel are members of the taxoid family of anti-mitotic drugs widely used as chemotherapeutic agents. Taxoids promote microtubule polymerization and stabilization. Their anti-mitotic properties are derived from their ability to bind tubulin and disrupt microtubule dynamics thereby inducing mitotic arrest and cell death.
Paclitaxel has activity against a broad band of tumour types, including breast, ovarian, lung, head and neck cancers. Paclitaxel also has activity in other malignancies that are refractory to conventional chemotherapy, including previously-treated lymphoma and small cell lung cancers and oesophageal, gastric, endometrial, bladder and germ cell tumours (Mekhail and Markman, 2002; Yamazaki et al., 1998). It is one of the most unique, and successful, chemotherapeutic agents currently used in the clinic for cancer treatment. However major problems associated with paclitaxel therapy exist. One of these is toxicity. Common toxicities of paclitaxel include total alopecia, hypersensitivity reactions, bone marrow suppression (principally neutropenia), arthralgia, myalgias, and peripheral neuropathy (Markman, 2003). The development of tolerance or drug resistance in tumour cells to paclitaxel is also a significant factor hindering the ongoing efficacy of paclitaxel treatment. To overcome resistance, typically the dosages of paclitaxel administered are increased thus leading to the development of side effects.
Accordingly, there is a clear need for alternative improved strategies for taxoid-based cancer treatments.
Another group of agents that target microtubules are the benzimidazole carbamates that have an opposing mode of action to the taxoids in that they inhibit microtubule polymerization rather than polymerize tubulin (Lacey, 1990; Lacey and Gill, 1994). Benzimidazole carbamates include albendazole, a broad spectrum anthelmintic used clinically for the treatment of a number of parasitic infections (Horton, 2000). The present inventors have previously found that albendazole has an anti-proliferative effect on a range of cancer cell lines in vitro and on cancers in animal models and clinical studies (WO 02/076454, the disclosure of which is incorporated herein by reference).
As disclosed herein, the present inventors have now surprisingly found that cancer cells highly resistant to paclitaxel and partially resistant to vincristine and colchicine are in fact hypersensitive to the anti-proliferative effects of albendazole. Further, albendazole potentiates the effect of paclitaxel in human cancer cells, both in paclitaxel-sensitive and paclitaxel-resistant cell lines, such that used in combination these drugs have an additive or synergistic effect in inhibiting cancer cell proliferation.